1,2,4-triazole derivatives, processes for the preparation thereof, and pharmaceutical compositions containing the same

ABSTRACT

A 1,2,4-triazole derivative of formula 1 or a non-toxic salt thereof, a preparation method thereof, and a pharmaceutical composition containing the derivative or the salt as an active ingredient are provided.

CROSS REFERENCE TO RELATED APPLICATION

This application is a 35 U.S.C. § 371 National Phase Entry Applicationfrom PCT/KR03/02574, filed Nov. 26, 2003, and designating the U.S.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a 1,2,4-triazole derivative or anon-toxic salt thereof, a method for preparing the same, and apharmaceutical composition containing the same as an active ingredient.

2. Description of the Related Art

Most nonsteroidal anti-inflammatory agents are responsible for blockingenzyme, cyclooxygenase (COX) or prostaglandin G/H synthase, to reduceinflammation, pain, or fever. In addition, they inhibit uteruscontraction caused by hormones and also inhibit growth of severalcancers. Cyclooxygenase-1 (COX-1) was first discovered in bovine. TheCOX-1 is constitutively expressed in a variety of cell types. Unlike theCOX-1, cyclooxygenase-2 (COX-2) is a recently discovered isoform ofcyclooxygenase that can be easily induced by mitogen, endotoxin,hormone, growth factor, or cytokine.

Prostaglandin is a potent mediator for various pathological andphysiological processes. The COX-1 plays important physiological rolessuch as in the release of endogenous prostaglandin, the maintenance ofthe shape and the function of stomach, and the blood circulation in thekidney. On the other hand, the COX-2 is induced by an inflammatoryfactor, hormone, a growth factor, or cytokine. Therefore, the COX-2 isinvolved in pathological processes of prostaglandin, unlike theconstitutive COX-1. In this regard, selective inhibitors of the COX-2produce fewer and less side effects in terms of action mechanism incomparison with conventional nonsteroidal anti-inflammatory agents. Inaddition, they reduce inflammation, pain, and fever and inhibit uteruscontraction caused by hormones and growth of several cancers. Inparticular, they are effective in decreasing side effects such asstomach toxicity and kidney toxicity. Still furthermore, they inhibitthe synthesis of contractile prostanoid, thereby leading to suppressionof the contraction of smooth muscles. Therefore, they help in preventingpremature birth, menstrual irregularity, asthma, and eosinophilicdisease.

In addition, it is anticipated that selective inhibitors of the COX-2would be effective in treating osteoporosis and glaucoma. Utility ofselective inhibitors of the COX-2 is well described in publications[John Vane, “Towards a Better Aspirin” in Nature, Vol. 367, pp215-216,1994; Bruno Battistini, Regina Botting and Y. S. Bakhle, “COX-1 andCOX-2: Toward the Development of More Selective NSAIDs” in Drug News andPerspectives, Vol. 7, pp501-512, 1994; Urology, Vol. 58, pp127, 2001;David B. Reitz and Karen Seibert, “Selective Cyclooxygenase Inhibitors”in Annual Reports in Medicinal Chemistry, James A. Bristol, Editor, Vol.30, pp179-188, 1995].

Various selective COX-2 inhibitors having different structures areknown. Among them, a selective COX-2 inhibitor having a diarylheterocyclic structure, i.e. a tricyclic structure has been widelystudied as a potent candidate. The diaryl heterocyclic structure has acentral ring and a sulfonamide or methylsulfone group attached to one ofthe aryl rings.

One selective COX-2 inhibitor, Celecoxib of formula 70 is disclosed inU.S. Pat. No. 5,466,823. The Celecoxib is a substituted pyrazolylbenzenesulfonamide derivative.

Another selective COX-2 inhibitor, Rofecoxib of formula 71 is disclosedin WO 95/00501. The Rofecoxib has a diary heterocyclic structure with acentral furanone ring.

Valdecoxib of formula 72 as another selective COX-2 inhibitor isdisclosed in U.S. Pat. No. 5,633,272. The Valdecoxib has aphenylsulfonamide moiety with a central isoxazole ring.

The selective COX-2 inhibitors of formulas 70 to 72 are effectiveinflammatory therapeutic agents with fewer and less side effects incomparison with conventional nonsteroidal anti-inflammatory agents.

SUMMARY OF THE INVENTION

An aspect of the present invention provides a 1,2.4-triazole derivativeof formula 1 or a non-toxic salt thereof.

Another aspect of the present invention provides a method for preparinga 1,2.4-triazole derivative or a non-toxic salt thereof.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising a 1,2.4-triazole derivative or a non-toxic saltthereof as an active ingredient for the treatment of fever, pain, andinflammation.

DETAILED DESCRIPTION OF THE INVENTION

According to an aspect of the present invention, there is provided a1,2.4-triazole derivative represented by formula 1:

-   -   wherein:    -   X represents methyl or amino;    -   Ar represents phenyl or phenyl substituted with one or more        radicals selected from C₁-C₆ alkoxy and halogen;    -   A represents O or S; and    -   R represents H, C₁-C₆ alkyl, trifluoro C₁-C₆ alkyl, C₃-C₆        cycloalkyl, C₁-C₆ alkyl substituted with cyano or halogen,        propagyl, allyl, or benzyl;    -   or a non-toxic salt thereof.

The 1,2,4-triazole derivative of formula 1 may be present in a form of anon-toxic salt. The term, “non-toxic salt” as used herein refers to apharmaceutically acceptable toxin-free salt, including an organic saltand an inorganic salt.

The 1,2,4-triazole derivative of formula 1 may be present in a form ofan organic acid salt or an inorganic acid salt.

Examples of the organic acid salt or the inorganic acid salt of the1,2,4-triazole derivative of formula 1 include, but are not limited to,a salt of acetic acid, adipic acid, aspartic acid, 1,5-naphthalenedisulfonic acid, benzene sulfonic acid, benzoic acid, camphor sulfonicacid, citric acid, 1,2-ethane disulfonic acid, ethane sulfonic acid,ethylenediaminetetraacetic acid, fumaric acid, glucoheptonic acid,gluconic acid, glutamic acid, hydroiodic acid, hydrobromic acid,hydrochloric acid, icethionic acid, lactic acid, maleic acid, malicacid, madelic acid, methane sulfonic acid, mucinic acid,2-naphthalenedisulfonic acid, nitric acid, oxalic acid, pentothenicacid, phosphoric acid, pivalric acid, propionic acid, salicylic acid,stearic acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, and 10-undecenoic acid. Preferably, asalt of succinic acid, hydrobromic acid, hydrochloric acid, maleic acid,methanesulfonic acid, phosphoric acid, sulfuric acid, or tartaric acidis used.

The 1,2,4-triazole derivative of the present invention preferablyincludes:

-   -   4-(3-mercapto-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;    -   4-(3-hydroxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;    -   4-[3-hydroxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-hydroxy-5-(4-ethoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-hydroxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-hydroxy-5-(4-bromophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-hydroxy-5-(3-fluoro-4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   1-(4-methanesulfonylphenyl)-5-phenyl-1H-1,2,4-triazole-3-ol;    -   1-(4-methanesulfonylphenyl)-5-(4-methoxyphenyl)-1H-1,2,4-triazole-3-ol;    -   4-(3-methoxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;    -   4-[3-methoxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-methoxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-methoxy-5-(4-bromophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-methoxy-5-(3-fluoro-4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-(3-methylthio-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;    -   4-(3-ethoxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;    -   4-[3-ethoxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-ethoxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-ethoxy-5-(3-fluoro-4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-(3-ethylthio-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;    -   4-[3-propoxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-propoxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-cyclopentyloxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-cyclopentyloxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-cyclohexyloxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-cyclohexyloxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-(3-isopropoxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;    -   4-[3-isopropoxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-isopropoxy-5-(-4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-(3-isopropylthio-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;    -   4-(3-allyloxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;    -   4-[3-allyloxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-allyloxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-cyanomethoxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-cyanomethoxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-(3-benzyloxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;    -   4-[3-benzyloxy-5-(3-fluoro-4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-(2-chloroethoxy)-5-phenyl-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-(2,2,2-trifluoroethoxy)-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-(2,2,2,-trifluoroethoxy)-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-cyclopropoxy-5-phenyl-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-prop-2-ynyloxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-[3-prop-2-ynyloxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;    -   4-(3-propy-2-nylthio-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;    -   1-(4-methanesulfonylphenyl)-3-methoxy-5-phenyl-1H-1,2,4-triazole;    -   1-(4-methanesulfonylphenyl)-3-methoxy-5-(4-methoxyphenyl)-1H-1,2,4-triazole;    -   1-(4-methanesulfonylphenyl)-3-ethoxy-5-phenyl-1H-1,2,4-triazole;    -   1-(4-methanesulfonylphenyl)-3-ethoxy-5-(4-methoxyphenyl)-1H-1,2,4-triazole;    -   1-(4-methanesulfonylphenyl)-3-isopropoxy-5-phenyl-1H-1,2,4-triazole;        and    -   1-(4-methanesulfonylphenyl)-3-isopropoxy-5-(4-methoxyphenyl)-1H-1,2,4-triazole.

According to another aspect of the present invention, there is providedcompound of formula 2 as an intermediate for the synthesis of the1,2,4-triazole derivative of formula 1:

-   -   wherein, Ar, A, and X are as defined in formula 1.

According to another aspect of the present invention, there is provideda method for preparing a 1,2,4-triazole derivative of formula 1b,comprising reacting compound of formula 1a with R′—Br or R′—I in thepresence of a base:

-   -   wherein:    -   X, Ar, and A are as defined in formula 1;    -   R′ represents C₁-C₆ alkyl, trifluoro C₁-C₆ alkyl, C₃-C₆        cycloalkyl, C₁-C₆ alkyl substituted with cyano or halogen,        propagyl, allyl, or benzyl.

The said reaction is preferably carried out in a polar solvent, whichincludes, but is not limited to DMF, dioxane, DMSO, methylpyrrolidinone,or m-xylene.

The reactions is preferably carried out at 0° C. to 110° C. The reactiontime is 5 minutes to 36 hours, depending on the reactants.

The base may be an organic base or an inorganic base. Among the organicbase, preferably triethyl amine, trimethyl amine, tripropyl amine,pyridine, or imidazole is used. Among the inorganic base, preferablysodium acetate, sodium hydroxide, sodium hydride, potassium hydroxide,sodium carbonate, or potassium carbonate is used. More preferably,sodium hydride is used.

According to another aspect of the present invention, there is provideda method for preparing a 1,2,4-triazole derivative of formula 1a,comprising refluxing a compound of formula 2 in a basic solvent to forma 1,2,4-triazole:

-   -   wherein, X, Ar, and A are as defined in formula 1.

The basic solvent is preferably potassium hydroxide, sodium hydroxide,or lithium hydroxide. More preferably, potassium hydroxide is used.

According to another aspect of the present invention, there is provideda method for preparing a compound of formula 2, comprising reacting acompound of formula 3 with a hydrazine derivative of formula 4 in thepresence of a base:

-   -   wherein, X, Y, and A are as defined in formula 1.

The said reaction is preferably carried out in a polar solvent, whichincludes, but is not limited to DMF, dioxane, DMSO, methylpyrrolidinone,or m-xylene.

The reactions is preferably carried out at 0° C. to 110° C. The reactiontime is 5 minutes to 36 hours depending on the reactants.

When the reaction is completed, the reaction resultant is extracted withwater and an organic solvent such as ethyl acetate, dichloromethane,tetrahydrofuran, or ether, to remove salts. The crude extract ispurified by silica gel column chromatography to give the compound offormula 2.

The base to be used herein is an organic base or an inorganic base.Preferably, the organic base is triethyl amine, trimethyl amine,tripropyl amine, pyridine, or imidazole. Preferably, the inorganic baseis sodium acetate, sodium hydroxide, sodium hydride, potassiumhydroxide, sodium carbonate, or potassium carbonate. More preferably,potassium carbonate is used.

The above compound of formual 3 may be prepared by reacting a benzamidederivative with a oxalyl chloride. The reaction is preferably carriedout in a solvent selected from the group consisting of dichloromethane,dichloroethane, and THF. The reactions is preferably carried out at anambient temperature or by reflux. The reaction time is 1 hour to 24hours depending on the reactants. When the reaction is completed, thereaction product is preferably obtained by distilling the solvent underreduced pressure without purification processes.

All crude products obtained from the above mentioned reactions arepurified via a conventional post-treatment process, for example,chromatography or recrystallization to thereby give final products.

A method for preparing a compound of formula 1 may be expressed in orderby the following scheme 1:

-   -   wherein, X, Y, A, and B are as defined in the above. A hydrazine        derivative to be used in the scheme 1 may be purchased as is or        in the form of their hydrochlorides

In methods for preparing compounds of the present invention, reactionconditions such as types and amounts of solvent, base, and reactants arenot limited to those as mentioned in the above. It is understood that aperson of ordinary skill in the art can easily prepare compounds of thepresent invention through any combination of synthesis methods asdescribed in the specification or as disclosed in known documents.

According to another aspect of the present invention, there is provideda pharmaceutical composition comprising a therapeutically effectiveamount of a 1,2,4-triazole derivative of formula 1 or a non-toxic saltthereof as an active ingredient and a pharmaceutically acceptablecarrier for treatment of fever, pain, and inflammation.

The pharmaceutical composition comprises a compound of formula 1 or anon-toxic salt thereof when it is a selective inhibitor ofcyclooxygenase-2. Therefore, the pharmaceutical composition can be usedas an antipyretic, an analgesic, and an anti-inflammatory agent, withreduced side effects.

Conventional nonsteroidal anti-inflammatory agents non-selectivelyinhibit the prostaglandin synthesis enzymes, cyclooxygenase-1 andcyclooxygenase-2. Therefore, various side effects may occur.

On the other hand, a compound of formula 1 and a non-toxic salt thereofselectively inhibit cyclooxygenase-2. Therefore, the side effects ofconventional nonsteroidal antipyretics, analgesics, andanti-inflammatory agents can be reduced.

The pharmaceutical composition of the present invention comprises acompound of formula 1 and/or a non-toxic salt thereof and apharmaceutically acceptable carrier or excipient. Therefore, thepharmaceutical composition may be used as a substitute for conventionalnonsteroidal anti-inflammatory agents. In particular, due to thereduction of the side effects of conventional nonsteroidal antipyretics,analgesics, and anti-inflammatory agents, the pharmaceutical compositionof the present invention is useful in treating patients with pepticulcer, gastritis, regional enteritis, ulcerative colitis,diverticullitis, gastrorrhagia, or hypoprothrombinemia.

The pharmaceutical composition of the present invention can be used inall inflammatory diseases associated with pathological prostaglandin andis particularly useful in treating osteoarthritis and rheumatoidarthritis which require high dosage of nonsteroidal anti-inflammatoryagents.

The pharmaceutical composition of the present invention can beadministered in the form of an adult dosage of 1 mg/day to 1000 mg/dayof the compound of formula 1. An adequate dosage is determined dependingon the degree of disease severity.

According to yet another aspect of the present invention, there isprovided a pharmaceutical composition comprising a therapeuticallyeffective amount of a 1,2,4-triazole derivative of formula 1 or anon-toxic salt thereof and a pharmaceutically acceptable carrier for thetreatment of cancers and dementia.

Recently, it was reported that nonsteroidal anti-inflammatory agents areeffective in the treatment of large intestine cancer [European Journalof Cancer, Vol 37, p2302, 2001], prostate cancer [Urology, Vol 58, p127,2001], and dementia [Exp. Opin. Invest Drugs, Vol 9, p671, 2000].Therefore, it is understood that the pharmaceutical composition of thepresent invention as a nonsteroidal anti-inflammatory agent can also beused for the treatment of these diseases.

The pharmaceutical composition for the treatment of cancers and dementiaof the present invention can be administered in the form of an adultdosage of 1 mg/day to 1000 mg/day of the compound of formula 1 or anon-toxic salt thereof. An adequate dosage is determined depending onthe degree of disease severity.

The pharmaceutical composition of the present invention may beadministered in the form of tablet, foam tablet, capsule, granule,powder, sustained-release tablet, sustained-release capsule (a singleunit formulation or a multiple unit formulation), intravenous andintramuscular injectable solution, infusion solution, suspension, orsuppository, or in other suitable dosage forms.

Sustained-release pharmaceutical dosage forms contain active ingredientswith or without an initial loading dose. They are wholly or partiallysustained-release pharmaceutical dosage forms to release activeingredients in a controlled manner.

Preferably, the pharmaceutical composition is orally administered.

The pharmaceutical composition further comprises a pharmaceuticallyacceptable excipient and/or diluent and/or adjuvant in pharmaceuticallyeffective amounts.

Examples of the excipient and adjuvant include gellatin, a natural sugarsuch as sucrose and lactose, lecitin, pectin, starch such as corn starchand amylose, cyclodextrin and cyclodextrin derivative, dextran,polyvinylpyrrolidone, polyvinyl acetate, Arabic gum, arginic acid,xylose, talc, salicylic acid, calcium hydrogen phosphate, cellulose,cellulose derivative such as methylcellulose, methoxypropyl cellulose,hydroxypropylmethyl cellulose, and hydroxypropylmethylcellulosephthalate, fatty acid having 12 to 22 carbon atoms, emulsifying agent,oil and fat, in particular, vegetable glycerol ester and polyglycerolester of saturated fatty acids, monohydric alcohol, polyhydric alcohol,polyglycol such as polyethylene glycol, aliphatic alcohol having 1 to 20carbon atoms, or aliphatic saturated or unsaturated fatty acid esterhaving 2 to 22 carbon atoms with polyhydric alcohols such as glycol,glycerol, diethylene glycol, 1,2-propylene glycol, sorbitol, andmannitol.

Other suitable adjuvants include a disintegrating agent. Examples of thedisintegrating agent include a cross-linked polyvinylpyrrolidone, sodiumcarboxymethyl starch, sodium carboxymethyl cellulose, andmicrocrystalline cellulose. A coating agent which is conventionally usedin this field may also be used. Examples of the coating agent includeacrylic acid and/or methacrylic acid and/or an ester polymer orcopolymer thereof, zein, ethyl cellulose, ethyl cellulose succinate, andShellac.

A plasticizer suitable for the coating agent is citric ester andtartaric ester, glycerol and glycerol ester, or polyethylene glycol withdifferent chain lengths.

A liquid composition such as solution and suspension is formulated inwater or a physiological acceptable organic solvent such as alcohol andaliphatic alcohol.

The liquid pharmaceutical composition may further comprise apreservative such as potassium solvate, methyl 4-hydroxybenzoate, andpropyl 4-hydroxybenzoate, an antioxidant such as ascorbic acid, and afragrant such as peppermint oil.

In addition, when the liquid pharmaceutical composition is formulated, aconventional solubilizer or emulsifier such as polyvinylpyrrolidone andpolysolvate 80 may be used.

Other examples of suitable excipients and adjuvants are disclosed in Dr.H. P. Fielder, “Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik undangrenzende Gebiete” [Encyclopaedia of auxiliaries for pharmacy,cosmetics and related fields].

Hereinafter, the present invention will be described more specificallyby examples. However, the following examples are provided only forillustration and thus the present invention is not limited to or bythem.

EXAMPLE 1 4-fluorobenzoylisocyanate

1.5 g of 4-fluorobenzamide was dissolved in 20 ml of dichloromethane and2.3 ml of oxalyl chloride was slowly added thereto at room temperature,and then the mixutre was heated and refluxed for 16 hours. When thereaction was completed, the reaction mixture was cooled to roomtemperature and the solvent was distilled under reduced pressure toproduce the titled compound as a oil. Without purification processes,next process was proceeded.

Mass(LOW EI)=165.0

EXAMPLE 2 4-methoxybenzoylisocyanate

The titled compound as a liquid was prepared in the same manner as inExample 1 except using 2.0 g of 4-methoxybenzamide instead of4-fluorobenzamide.

Mass(LOW EI)=177.04

EXAMPLE 3 4-ethoxybenzoylisocyanate

The titled compound as a liquid was prepared in the same manner as inExample 1 except using 2.0 g of 4-ethoxybenzamide instead of4-fluorobenzamide.

Mass(LOW EI)=191.04

EXAMPLE 4 4-bromobenzoylisocyanate

The titled compound as a liquid was prepared in the same manner as inExample 1 except using 2.0 g of 4-bromobenzamide instead of4-fluorobenzamide.

Mass(LOW EI)=225.0

EXAMPLE 5 3-fluoro-4-methoxybenzoylisocyanate

The titled compound as a liquid was prepared in the same manner as inExample 1 except using 2.0 g of 3-fluoro-4-methoxybenzamide instead of4-fluorobenzamide.

Mass(LOW EI)=195.0

EXAMPLE 6 1-benzoyl-3-(4-aminosulfonylbenzenehydrazinyl)-urea

3.1 g of benzoylisocyanate was dissolved in 20 ml of DMF and then 1 eqof 4-aminosulfonylbenzenehydrazine hydrochloride and 2 eq of potassiumcarbonate were added thereto and stirred for 4 hours at roomtemperature. When the reaction was completed, 100 ml of water was addedthereto to form yellow precipitate. The yellow precipitate was washedwith 30 ml of EA/n-Hex(1/6) to give 4.70 g of the titled compound as apale yellow solid (yield 66%).

Mass(LOW EI)=334.0

EXAMPLE 7 1-(4-fluorobenzoyl)-3-(4-aminosulfonylbenzenehydrazinyl)-urea

2.85 g (yield 67%) of the titled compound as a yellow solid was preparedin the same manner as in Example 6 except using 2.0 g of4-fluorobenzoylisocyanate instead of benzoylisocyanate.

Mass(LOW EI)=352.0

EXAMPLE 8 1-(4-methoxybenzoyl)-3-(4-aminosulfonylbenzenehydrazinyl)-urea

4.45 g (yield 72%) of the titled compound as a yellow solid was preparedin the same manner as in Example 6 except using 3.0 g of4-methoxybenzoyl isocyanate instead of benzoylisocyanate.

Mass(LOW EI)=364.0

EXAMPLE 9 1-(4-bromobenzoyl)-3-(4-aminosulfonylbenzenehydrazinyl)-urea

3.50 g (yield 63%) of the titled compound as a yellow solid was preparedin the same manner as in Example 6 except using 3.0 g of4-bromobenzoylisocyanate instead of benzoylisocyanate.

Mass(LOW EI)=412.0

EXAMPLE 10 1-(4-ethoxybenzoyl)-3-(4-aminosulfonylbenzenehydrazinyl)-urea

4.50 g (yield 70%) of the titled compound as a yellow solid was preparedin the same manner as in Example 6 except using 3.0 g of4-ethoxybenzoylisocyanate instead of benzoylisocyanate.

Mass(LOW EI)=378.0

EXAMPLE 111-(3-fluoro-4-methoxybenzoyl)-3-(4-aminosulfonylbenzenehydrazinyl)-urea

3.20 g (yield 55%) of the titled compound as a yellow solid was preparedin the same manner as in Example 6 except using 3.0 g of3-fluoro-4-methoxybenzoylisocyanate instead of benzoylisocyanate.

Mass(LOW EI)=382.0

EXAMPLE 12 1-benzoyl-3-(4-aminosulfonylbenzenehydrazinyl)-thiourea

4.50 g (yield 70%) of the titled compound as a yellow solid was preparedin the same manner as in Example 6 except using 3.0 g ofbenzoylisothiocyanate instead of benzoylisocyanate.

Mass(LOW EI)=350.0

EXAMPLE 13 1-benzoyl-3-(4-methanesulfonylbenzenehydrazinyl)-urea

4.20 g (yield 79%) of the titled compound as a yellow solid was preparedin the same manner as in Example 6 except using 3.0 g of4-methanesulfonylbenzenehydrazine hydrochloride instead of4-aminosulfonylbenzenehydrazine hydrochloride.

Mass(LOW EI)=330.0

EXAMPLE 141-(4-methoxybenzoyl)-3-(4-methanesulfonylbenzenehydrazinyl)-urea

3.70 g (yield 60%) of the titled compound as a yellow solid was preparedin the same manner as in Example 13 except using 3.0 g of4-methoxybenzoylisocyanate instead of benzoylisocyanate.

Mass(LOW EI)=363.0

EXAMPLE 15 4-(3-hydroxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide

40 ml of 10% KOH solution was slowly added to 5 g of1-benzoyl-3-(4-aminosulfonylbenzenehydrazinyl)-urea and then refluxedfor 10 hours. When the reaction was completed, the resultant was pouredinto 100 ml of cold water to form a white solid precipitate at thebottom of the solution. The white precipitate was filtered and thenwashed with 50 ml of cold water and 50 ml of IPA (1× each) to give 3.60g (yield 75%) of the titled compound as a pale yellow solid.

¹H NMR (DMSO-d6, 400 MHz)

7.40-7.50 (m, 7H), 7.55 (d, 2H, J=8.7 Hz), 7.88 (d, 2H, J=8.7 Hz)

EXAMPLE 164-[3-hydroxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

3.8 g (yield 75%) of the titled compound as a yellow solid was preparedin the same manner as in Example 15 except using 5.1 g of1-(4-methoxybenzoyl)-3-(4-aminosulfonylbenzenehydrazinyl)-urea insteadof 1-benzoyl-3-(4-aminosulfonylbenzenehydrazinyl)-urea.

¹H NMR (DMSO-d6, 400 MHz)

3.88 (s, 3H), 7.00 (d, 2H, J=8.9 Hz), 7.30 (d, 2H, J=8.9 Hz), 7.40 (s,2H), 7.60 (d, 2H, J=8.6 Hz), 7.95 (d, 2H, J=8.6 Hz)

EXAMPLE 174-[3-hydroxy-5-(4-ethoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

3.8 g (yield 65%) of the titled compound as a yellow solid was preparedin the same manner as in Example 15 except using 5.0 g of1-(4-ethoxybenzoyl)-3-(4-aminosulfonylbenzenehydrazinyl)-urea instead of1-benzoyl-3-(4-aminosulfonylbenzenehydrazinyl)-urea.

¹H NMR (DMSO-d6, 400 MHz)

1.40 (t, 3H, J=6.9 Hz), 3.88 (q, 2H, J=6.9 Hz), 4.35 (q, 2H, J=6.9 Hz),7.00 (d, 2H, J=8.9 Hz), 7.30 (d, 2H, J=8.9 Hz), 7.40 (s, 2H), 7.60 (d,2H, J =8.6 Hz), 7.95 (d, 2H, J=8.6 Hz)

EXAMPLE 184-[3-hydroxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

4.8 g (yield 75%) of the titled compound as a yellow solid was preparedin the same manner as in Example 15 except using 6.6 g of1-(4-fluorobenzoyl)-3-(4-aminosulfonylbenzenehydrazinyl)-urea instead of1-benzoyl-3-(4-aminosulfonylbenzenehydrazinyl)-urea.

¹H NMR (DMSO-d6, 400 MHz)

6.90 (d, 2H, J=8.9 Hz), 7.20 (d, 2H, J=8.9 Hz), 7.40 (s, 2H), 7.60 (d,2H, J=8.6 Hz), 7.95 (d, 2H, J=8.6 Hz)

EXAMPLE 194-[3-hydroxy-5-(4-bromophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

3.5 g (yield 61%) of the titled compound as a yellow solid was preparedin the same manner as in Example 15 except using 6.0 g of1-(4-bromobenzoyl)-3-(4-aminosulfonylbenzenehydrazinyl)-urea instead of1-benzoyl-3-(4-aminosulfonylbenzenehydrazinyl)-urea.

¹H NMR (DMSO-d6, 400 MHz)

7.30 (d, 2H, J=8.9 Hz), 7.40 (d, 2H, J=8.9 Hz), 7.45 (s, 2H), 7.60 (d,2H, J=8.6 Hz), 7.95 (d, 2H, J=8.6 Hz)

EXAMPLE 204-[3-hydroxy-5-(3-fluoro-4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

1.80 g (yield 70%) of the titled compound as a yellow solid was preparedin the same manner as in Example 15 except using 2.70 g of1-(3-fluoro-4-methoxybenzoyl)-3-(4-aminosulfonylbenzenehydrazinyl)-ureainstead of 1-benzoyl-3-(4-aminosulfonylbenzenehydrazinyl)-urea.

¹H NMR (DMSO-d6, 400 MHz)

3.95 (s, 3H), 7.15-7.25 (m, 2H), 7.30 (dd, 1H, J=1.8, 12.9 Hz), 7.50 (s,2H), 7.55 (d, 2H, J=8.7 Hz), 7.90 (d, 2H, J=8.7 Hz)

EXAMPLE 214-(3-mercapto-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide

3.8 g (yield 65%) of the titled compound as a yellow solid was preparedin the same manner as in Example 15 except using 5.0 g of1-benzoyl-3-(4-aminosulfonylbenzenehydrazinyl)-thiourea instead of1-benzoyl-3-(4-aminosulfonylbenzenehydrazinyl)-urea.

¹H NMR (DMSO-d6, 400 MHz)

7.40-7.50 (m, 7H), 7.55 (d, 2H, J=8.7 Hz), 7.88 (d, 2H, J=8.7 Hz)

EXAMPLE 22 1-(4-methanesulfonylphenyl)-5-phenyl-1H-1,2,4-triazole-3-ol

3.6 g (yield 65%) of the titled compound as a yellow solid was preparedin the same manner as in Example 15 except using 5.0 g of1-benzoyl-3-(4-methanesulfonylbenzenehydrazinyl)-urea instead of1-benzoyl-3-(4-aminosulfonylbenzenehydrazinyl)-urea.

¹H NMR (DMSO-d6, 400 MHz)

3.10 (s, 3H), 7.40-7.50 (m, 7H), 7.50 (d, 2H, J=8.7 Hz), 7.80 (d, 2H,J=8.7 Hz)

EXAMPLE 231-(4-methanesulfonylphenyl)-5-(4-methoxyphenyl)-1H-1,2,4-triazole-3-ol

3.3 g (yield 69%) of the titled compound as a yellow solid was preparedin the same manner as in Example 15 except using 5.0 g of1-(4-methoxybenzoyl)-3-(4-methanesulfonylbenzenehydrazinyl)-urea insteadof 1-benzoyl-3-(4-aminosulfonylbenzenehydrazinyl)-urea.

¹H NMR (DMSO-d6, 400 MHz)

3.98 (s, 3H) 7.00 (d, 2H, J=8.9 Hz), 7.30 (d, 2H, J=8.9 Hz), 7.40 (s,2H), 7.60 (d, 2H, J=8.6 Hz), 7.95 (d, 2H, J=8.6 Hz)

EXAMPLE 244-[3-methoxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

500 mg of4-[3-hydroxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamideprepared in the above Example 16, was dissolved in 10 ml of DMF and then1.05 eq of NaH was slowly added thereto. Afterwards 1.5 eq ofiodomethane was added to the mixture and then stirred for 3 hours at thesame temperature. When the reaction was completed, the resultant waspoured into 100 ml of cold water to form precipitate. The precipitatewas filtered and then washed with 100 ml of cold ether and 100 ml ofcold water (1× each) to give 385 mg (yield 75%) of the titled compoundas a white solid.

¹H NMR (DMSO-d6, 400 MHz)

3.80 (s, 3H), 3.98 (s, 3H) 7.00 (d, 2H, J=8.9 Hz), 7.30 (d, 2H, J=8.9Hz), 7.40 (s, 2H), 7.60 (d, 2H, J=8.6 Hz), 7.95 (d, 2H, J=8.6 Hz)

EXAMPLE 25 4-(3-methoxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide

281 mg (yield 73%) of the titled compound as a yellow solid was preparedin the same manner as in Example 24 except using 300 mg of4-(3-hydroxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide instead of4-[3-hydroxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide.

¹H NMR (DMSO-d6, 400 MHz)

3.10 (s, 3H), 7.40-7.45 (m, 2H), 7.47 (s, 2H). 7.48-7.52 (m, 3H), 7.58(d, 2H, J=8.7 Hz), 7.90 (d, 2H, J=8.7 Hz)

EXAMPLE 264-[3-methoxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

240 mg (yield 67%) of the titled compound as a yellow solid was preparedin the same manner as in Example 24 except using 300 mg of4-[3-hydroxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamideinstead of4-[3-hydroxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide.

¹H NMR (DMSO-d6, 400 MHz)

3.80 (s, 3H), 7.30 (d, 2H, J=7.0 Hz), 7.45-7.60 (m, 6H), 8.00 (d, 2H,J=7.0 Hz)

EXAMPLE 274-[3-methoxy-5-(4-bromophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

200 mg (yield 57%) of the titled compound as a yellow solid was preparedin the same manner as in Example 24 except using 300 mg of4-[3-hydroxy-5-(4-bromophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamideinstead of4-[3-hydroxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide.

¹H NMR (DMSO-d6, 400 MHz)

3.80 (s, 3H), 7.40 (d, 2H, J=7.0 Hz), 7.45-7.50 (m, 4H), 7.65 (d, 2H,J=8.7 Hz), 8.00 (d, 2H, J=8.7 Hz)

EXAMPLE 284-[3-methoxy-5-(3-fluoro-4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

150 mg (yield 76%) of the titled compound as a yellow solid was preparedin the same manner as in Example 24 except using 200 mg of4-[3-hydroxy-5-(3-fluoro-4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamideinstead of4-[3-hydroxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide.

¹H NMR (DMSO-d6, 400 MHz)

3.80 (s, 3H), 4.90 (s, 3H), 7.15-22 (m, 2H), 7.30 (dd, J=1.8, 12.9 Hz),7.50 (s, 2H), 7.55 (d, 2H, J=8.7 Hz), 7.90 (d, 2H, J=8.7 Hz)

EXAMPLE 294-(3-methylthio-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide

120 mg (yield 61%) of the titled compound as a yellow solid was preparedin the same manner as in Example 24 except using 200 mg of4-(3-mercapto-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide insteadof4-[3-hydroxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide.

¹H NMR (DMSO-d6, 400 MHz)

3.10 (s, 3H), 7.40-7.45 (m, 2H), 7.47 (s, 2H). 7.48-7.52 (m, 3H), 7.58(d, 2H, J=8.7 Hz), 7.90 (d, 2H, J=8.7 Hz)

EXAMPLE 304-[3-ethoxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

200 mg (yield 63%) of the titled compound as a yellow solid was preparedin the same manner as in Example 24 except using iodoethane instead ofiodomethane.

¹H NMR (DMSO-d6, 400 MHz)

1.50 (t, 3H, J=7.0 Hz), 3.80 (s, 3H), 4.20 (q, 2H, J=7.0 Hz), 6.90 (d,2H, J=8.6 Hz), 7.25 (d, 2H, J=8.6 Hz), 7.45 (s, 2H), 7.60 (d, 2H, J=8.3Hz), 7.95 (d, 2H, J=8.3 Hz)

EXAMPLE 31 4-(3-ethoxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide

160 mg (yield 50%) of the titled compound as a yellow solid was preparedin the same manner as in Example 25 except using iodoethane instead ofiodomethane.

¹H NMR (DMSO-d6, 400 MHz)

1.50 (t, 3H, J=7.0 Hz), 4.20 (q, 2H, J=7.0 Hz), 7.40-7.45 (m, 2H), 7.47(s, 2H). 7.48-7.52 (m, 3H), 7.58 (d, 2H, J=8.7 Hz), 7.90 (d, 2H, J=8.7Hz)

EXAMPLE 324-[3-ethoxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

200 mg (yield 63%) of the titled compound as a yellow solid was preparedin the same manner as in Example 26 except using iodoethane instead ofiodomethane.

¹H NMR (DMSO-d6, 400 MHz)

1.45 (t, 3H, J=6.7 Hz), 4.20 (q, 2H, J=6.7 Hz), 7.30 (d, 2H, J=7.0 Hz),7.45-7.60 (m, 6H), 8.00 (d, 2H, J=7.0 Hz)

EXAMPLE 334-[3-ethoxy-5-(3-fluoro-4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

100 mg (yield 45%) of the titled compound as a yellow solid was preparedin the same manner as in Example 28 except using iodoethane instead ofiodomethane.

¹H NMR (DMSO-d6, 400 MHz)

1.35 (t, 3H, J=6.1 Hz), 3.80 (s, 3H), 4.84 (q, 2H, J=6.1 Hz), 7.15-22(m, 2H), 7.30 (dd, J=1.8, 12.9 Hz), 7.50 (s, 2H), 7.55 (d, 2H, J=8.7Hz), 7.90 (d, 2H, J=8.7 Hz)

EXAMPLE 344-(3-ethylthio-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide

110 mg (yield 55%) of the titled compound as a yellow solid was preparedin the same manner as in Example 29 except using iodoethane instead ofiodomethane.

¹H NMR (DMSO-d6, 400 MHz)

1.50 (t, 3H, J=7.0 Hz), 4.20 (q, 2H, J=7.0 Hz), 7.40-7.45 (m, 2H), 7.47(s, 2H). 7.48-7.52 (m, 3H), 7.58 (d, 2H, J=8.7 Hz), 7.90 (d, 2H, J=8.7Hz)

EXAMPLE 354-[3-propoxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

160 mg (yield 51%) of the titled compound as a yellow solid was preparedin the same manner as in Example 24 except using iodopropane instead ofiodomethane.

¹H NMR (DMSO-d6, 400 MHz)

1.0 (t, 3H, J=7.3 Hz), 1.80 (dt, 2H, J=6.5, 7.3 Hz), 3.80 (s, 3H), 4.25(t, 2H, J=6.5 Hz)1, 6.90 (d, 2H, J=8.6 Hz), 7.25 (d, 2H, J=8.6 Hz), 7.45(s, 2H), 7.60 (d, 2H, J=8.3 Hz), 7.95 (d, 2H, J=8.3 Hz)

EXAMPLE 364-[3-propoxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

200 mg (yield 63%) of the titled compound as a yellow solid was preparedin the same manner as in Example 26 except using iodopropane instead ofiodomethane.

¹H NMR (DMSO-d6, 400 MHz)

1.0 (t, 3H, J=7.3 Hz), 1.80 (dt, 2H, J=6.5, 7.3 Hz), 4.25 (t, 2H, J=6.5Hz), 7.30 (d, 2H, J=7.0 Hz), 7.45-7.60 (m, 6H), 8.00 (d, 2H, J=7.0 Hz)

EXAMPLE 374-[3-cyclopentyloxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

150 mg (yield 45%) of the titled compound as a yellow solid was preparedin the same manner as in Example 24 except using cyclopentyl bromideinstead of methy liodide.

¹H NMR (DMSO-d6, 400 MHz)

1.60-2.00 (m, 8H), 3.80 (s, 3H), 5.10 (t, 1H, J=4.8 Hz), 7.00 (d, 2H,J=8.7 Hz), 7.30 (d, 2H, J=8.7 Hz), 7.45 (s, 2H), 7.60 (d, 2H, J=6.7 Hz),8.00 (d, 2H, J=6.7 Hz)

EXAMPLE 384-[3-cyclopentyloxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

100 mg (yield 43%) of the titled compound as a yellow solid was preparedin the same manner as in Example 26 except using cyclopentyl bromideinstead of iodomethane.

¹H NMR (DMSO-d6, 400 MHz)

1.60-2.00 (m, 8H), 3.80 (s, 3H), 5.10 (t, 1H, J=4.8 Hz), 7.30 (d, 2H,J=7.0 Hz), 7.45-7.60 (m, 6H), 8.00 (d, 2H, J=7.0 Hz)

EXAMPLE 394-[3-cyclohexyloxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

165 mg (yield 47%) of the titled compound as a yellow solid was preparedin the same manner as in Example 24 except using cyclohexyl bromideinstead of iodomethane.

¹H NMR (DMSO-d6, 400 MHz)

1.30 (bs, 2H), 1.50 (bs, 2H), 1.70 (bs, 2H), 2.00 (bs, 2H), 3.80 (s,3H), 4.60 (bs, 1H), 7.00 (d, 2H, J=8.7 Hz), 7.30 (d, 2H, J=8.7 Hz), 7.45(s, 2H), 7.60 (d, 2H, J=6.7 Hz), 8.00 (d, 2H, J=6.7 Hz)

EXAMPLE 404-[3-cyclohexyloxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

120 mg (yield 48%) of the titled compound as a yellow solid was preparedin the same manner as in Example 26 except using cyclohexyl bromideinstead of iodomethane.

¹H NMR (DMSO-d6, 400 MHz)

1.30 (bs, 2H), 1.50 (bs, 2H), 1.70 (bs, 2H), 2.00 (bs, 2H), 3.80 (s,3H), 4.60 (bs, 1H), 7.30 (d, 2H, J=7.0 Hz), 7.45-7.60 (m, 6H), 8.00 (d,2H, J=7.0 Hz)

EXAMPLE 414-[3-cyanomethoxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

190 mg (yield 53%) of the titled compound as a yellow solid was preparedin the same manner as in Example 24 except using 1-iodoacetonitrileinstead of methyliodide.

¹H NMR (DMSO-d6, 400 MHz)

5.20 (s, 2H), 7.00 (d, 2H, J=8.7 Hz), 7.30 (d, 2H, J=8.7 Hz), 7.45 (s,2H), 7.60 (d, 2H, J=6.7 Hz), 8.00 (d, 2H, J=6.7 Hz)

EXAMPLE 424-[3-cyanomethoxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

120 mg (yield 48%) of the titled compound as a yellow solid was preparedin the same manner as in Example 26 except using 1-iodoacetonitrileinstead of iodomethane.

¹H NMR (DMSO-d6, 400 MHz)

5.20 (s, 2H), 7.30 (d, 2H, J=7.0 Hz), 7.45-7.60 (m, 6H), 8.00 (d, 2H,J=7.0 Hz)

EXAMPLE 434-[3-prop-2-ynyloxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

190 mg (yield 53%) of the titled compound as a yellow solid was preparedin the same manner as in Example 24 except using propagyl bromideinstead of iodomethane.

¹H NMR (DMSO-d6, 400 MHz)

3.80 (s, 3H), 4.20 (s, 1H), 5.00 (s, 2H), 7.00 (d, 2H, J=8.7 Hz), 7.30(d, 2H, J=8.7 Hz), 7.45 (s, 2H), 7.60 (d, 2H, J=6.7 Hz), 8.00 (d, 2H,J=6.7 Hz)

EXAMPLE 444-[3-prop-2-ynyloxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

80 mg (yield 34%) of the titled compound as a yellow solid was preparedin the same manner as in Example 26 except using propagyl bromideinstead of methyliodide.

¹H NMR (DMSO-d6, 400 MHz)

4.20 (s, 1H), 5.00 (s, 2H) 7.30 (d, 2H, J=7.0 Hz), 7.45-7.60 (m, 6H),8.00 (d, 2H, J=7.0 Hz)

EXAMPLE 454-(3-prop-2-ynylthio-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide

80 mg (yield 34%) of the titled compound as a yellow solid was preparedin the same manner as in Example 29 except using propagyl bromideinstead of iodomethane.

¹H NMR (DMSO-d6, 400 MHz)

4.20 (s, 1H), 5.00 (s, 2H), 7.40-7.45 (m, 2H), 7.47 (s, 2H). 7.48-7.52(m, 3H), 7.58 (d, 2H, J=8.7 Hz), 7.90 (d, 2H, J=8.7 Hz)

EXAMPLE 464-[3-isopropoxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

210 mg (yield 65%) of the titled compound as a yellow solid was preparedin the same manner as in Example 24 except using 2-iodopropane insteadof iodomethane.

¹H NMR (DMSO-d6, 400 MHz)

1.20 (d, 6H, J=5.9 Hz), 3.80 (s, 3H), 4.95 (t, 1H, J=5.9 Hz), 5.15 (bs,2H), 6.75 (d, 2H, J=8.8 Hz), 7.35 (d, 2H, J=8.8 Hz), 7.55 (d, 2H, J=8.5Hz), 7.95 (d, 2H, J=8.5 Hz)

EXAMPLE 474-(3-isopropoxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide

135 mg (yield 48%) of the titled compound as a yellow solid was preparedin the same manner as in Example 25 except using 2-iodopropane insteadof iodomethane.

¹H NMR (DMSO-d6, 400 MHz)

1.20 (d, 6H, J=5.9 Hz), 4.95 (t, 1H, J=5.9 Hz), 5.15 (bs, 2H), 7.40-7.45(m, 2H), 7.47 (s, 2H). 7.48-7.52 (m, 3H), 7.58 (d, 2H, J=8.7 Hz), 7.90(d, 2H, J=8.7 Hz)

EXAMPLE 484-[3-isopropoxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

200 mg (yield 63%) of the titled compound as a yellow solid was preparedin the same manner as in Example 26 except using 2-iodopropane insteadof iodomethane.

¹H NMR (DMSO-d6, 400 MHz)

1.20 (d, 6H, J=5.9 Hz), 4.95 (t, 1H, J=5.9 Hz), 5.15 (bs, 2H), 7.30 (d,2H, J=7.0 Hz), 7.45-7.60 (m, 6H), 8.00 (d, 2H, J=7.0 Hz)

EXAMPLE 494-(3-isopropylthio-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide

110 mg (yield 55%) of the titled compound as a yellow solid was preparedin the same manner as in Example 29 except using 2-iodopropane insteadof iodomethane.

¹H NMR (DMSO-d6, 400 MHz)

1.20 (d, 6H, J=5.9 Hz), 4.95 (t, 1H, J=5.9 Hz), 5.15 (bs, 2H), 7.40-7.45(m, 2H), 7.47 (s, 2H). 7.48-7.52 (m, 3H), 7.58 (d, 2H, J=8.7 Hz), 7.90(d, 2H, J=8.7 Hz)

EXAMPLE 504-[3-benzyloxy-5-(3-fluoro-4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

100 mg (yield 35%) of the titled compound as a yellow solid was preparedin the same manner as in Example 28 except using benzyl bromide insteadof iodomethane.

¹H NMR (DMSO-d6, 400 MHz)

3.85 (s, 3H), 4.90 (s, 2H), 5.45 (s, 2H), 6.85 (t, 1H), J=8.7 Hz), 7.20(d, 1H, J=8.3 hz), 7.30-7.45 (m, 3H), 7.50 (m, 4H), 8.05 (d, 2H, J=8.7Hz)

EXAMPLE 514-(3-benzyloxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide

140 mg (yield 55%) of the titled compound as a yellow solid was preparedin the same manner as in Example 25 except using benzyl bromide insteadof iodomethane.

Mass (Low EI)=406.0

EXAMPLE 524-[3-allyloxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

150 mg (yield 64%) of the titled compound as a yellow solid was preparedin the same manner as in Example 24 except using allyl bromide insteadof iodomethane.

¹H NMR (CDCl3, 400 MHz)

3.80 (s, 3H), 4.80 (dt, 2H, J=1.5, 5.5 Hz), 5.00 (s, 2H), 5.40 (dd, 1H,J=1.3, 10.4 Hz), 5.60 (dd, 1H, J=1.3, 15.7 Hz), 6.10-6.20 (m, 1H), 6.75(d, 2H, J=8.8 Hz), 7.35 (d, 2H, J=8.8 Hz), 7.55 (d, 2H, J=8.5 Hz), 7.95(d, 2H, J=8.5 Hz)

EXAMPLE 534-(3-allyloxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide

125 mg (yield 58%) of the titled compound as a yellow solid was preparedin the same manner as in Example 25 except using allyl bromide insteadof iodomethane.

¹H NMR (CDCl3, 400 MHz)

4.80 (dt, 2H, J=1.5, 5.5 Hz), 5.00 (s, 2H), 5.40 (dd, 1H, J=1.3, 10.4Hz), 5.60 (dd, 1H, J=1.3, 15.7 Hz), 6.10-6.20 (m, 1H), 7.40-7.45 (m,2H), 7.47 (s, 2H). 7.48-7.52 (m, 3H), 7.58 (d, 2H, J=8.7 Hz), 7.90 (d,2H, J=8.7 Hz)

EXAMPLE 544-[3-allyloxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

200 mg (yield 63%) of the titled compound as a yellow solid was preparedin the same manner as in Example 26 except using allyl bromide insteadof iodomethane.

¹H NMR (DMSO-d6, 400 MHz)

4.80 (dt, 2H, J=1.5, 5.5 Hz), 5.40 (dd, 1H, J=1.3, 10.4 Hz), 5.60 (dd,1H, J=1.3, 15.7 Hz), 6.10-6.20 (m, 1H), 7.30 (d, 2H, J=7.0 Hz),7.45-7.60 (m, 6H), 8.00 (d, 2H, J=7.0 Hz)

EXAMPLE 554-[3-(2,2,2-trifluoroethoxy)-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

90 mg (yield 34%) of the titled compound as a yellow solid was preparedin the same manner as in Example 24 except using1,1,1-trifluoro-2-bromoethane instead of iodomethane.

¹H NMR (DMSO-d6, 400 MHz)

3.80 (s, 3H), 4.80 (q, 2H, J=8.2 Hz), 6.75 (d, 2H, J=8.8 Hz), 7.35 (d,2H, J=8.8 Hz), 7.55 (d, 2H, J=8.5 Hz), 7.95 (d, 2H, J=8.5 Hz)

EXAMPLE 564-[3-(2,2,2-trifluoroethoxy)-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide

85 mg (yield 54%) of the titled compound as a yellow solid was preparedin the same manner as in Example 26 except using1,1,1-trifluoro-2-bromoethane instead of iodomethane.

¹H NMR (DMSO-d6, 400 MHz)

4.80 (q, 2H, J=8.2 Hz), 7.30 (d, 2H, J=7.0 Hz), 7.45-7.60 (m, 6H), 8.00(d, 2H, J=7.0 Hz)

EXAMPLE 574-[3-(2-chloroethoxy)-5-phenyl-1,2,4-triazole-1-yl]-benzenesulfonamide

106 mg (yield 48%) of the titled compound as a yellow solid was preparedin the same manner as in Example 25 except using 2-chloro-1-iodoethaneinstead of iodomethane.

Mass (LOW EI)=364.1

EXAMPLE 584-[3-cyclopropoxy-5-phenyl-1,2,4-triazole-1-yl]-benzenesulfonamide

86 mg (yield 58%) of the titled compound as a yellow solid was preparedin the same manner as in Example 25 except using cyclopropyl bromideinstead of iodomethane.

Mass (LOW EI)=356.2

EXAMPLE 591-(4-methanesulfonylphenyl)-3-methoxy-5-(4-methoxylphenyl)-1H-1,2,4-triazole

160 mg (yield 78%) of the titled compound as a yellow solid was preparedin the same manner as in Example 24 except using 200 mg of1-(4-methanesulfonylphenyl)-5-(4-methoxyphenyl)-1H-1,2,4-triazole-3-olinstead of4-[3-hydroxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide.

¹H NMR (DMSO-d6, 400 MHz)

3.10 (s, 3H), 3.98 (s, 6H) 7.00 (d, 2H, J=8.9 Hz), 7.30 (d, 2H, J=8.9Hz), 7.60 (d, 2H, J=8.6 Hz), 7.95 (d, 2H, J=8.6 Hz)

EXAMPLE 601-(4-methanesulfonylphenyl)-3-methoxy-5-phenyl-1H-1,2,4-triazole

73 mg (yield 69%) of the titled compound as a yellow solid was preparedin the same manner as in Example 25 except using 100 mg of1-(4-methanesulfonylphenyl)-5-phenyl-1H-1,2,4-triazole-3-ol instead of4-(3-hydroxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide.

¹H NMR (DMSO-d6, 400 MHz)

3.10 (s, 3H), 3.98 (s, 3H), 7.40-7.45 (m, 2H), 7.48-7.52 (m, 3H), 7.58(d, 2H, J=8.7 Hz), 7.90 (d, 2H, J=8.7 Hz)

EXAMPLE 611-(4-methanesulfonylphenyl)-3-ethoxy-5-(4-methoxylphenyl)-1H-1,2,4-triazole

160 mg (yield 68%) of the titled compound as a yellow solid was preparedin the same manner as in Example 59 except using iodoethane instead ofiodomethane.

Mass (LOW EI)=373.1

EXAMPLE 621-(4-methanesulfonylphenyl)-3-ethoxy-5-phenyl-1H-1,2,4-triazole

73 mg (yield 69%) of the titled compound as a yellow solid was preparedin the same manner as in Example 60 except using iodoethane instead ofiodomethane.

Mass (LOW EI)=343.1

EXAMPLE 631-(4-methanesulfonylphenyl)-3-isopropoxy-5-(4-methoxyphenyl)-1H-1,2,4-triazole

120 mg (yield 58%) of the titled compound as a yellow solid was preparedin the same manner as in Example 59 except using 2-iodopropane insteadof iodomethane.

Mass (LOW EI)=387.1

EXAMPLE 641-(4-methanesulfonylphenyl)-3-isopropoxy-5-phenyl-1H-1,2,4-triazole

63 mg (yield 59%) of the titled compound as a yellow solid was preparedin the same manner as in Example 60 except using 2-iodopropane insteadof iodomethane.

Mass (LOW EI)=357.1

Experiments

-   -   1. Evaluation of Selective COX-2 Inhibitory Activity    -   1) Method

In order to pharmacologically determine the selective COX-2 inhibitoryactivity, the percentages of the COX-1 and COX-2 inhibition of thecompounds of the present invention illustrated in the Examples weremeasured by the following methods.

a. Assay for the COX-1 Inhibitory Activity Using U-937

U-937 human lymphoma cells (Korean Cell Line Bank, Seoul, Korea,Accession Number: 21593) were cultured and centrifuged. The collectedcells were diluted with HBSS (×1, Hank's balanced salt solution) to aconcentration of 1×10⁶ cells/ml. 1 ml of the dilute cell solution wasplaced into each well of 12-well plates. 5 μl of 1 μM solution of a testcompound in DMSO and 5 μl of DMSO as a control were added to the wells.The wells were incubated in CO₂ incubator at 37° C. for 15 minutes.Separately, 10 mM stock solution of arachidonic acid in ethanol wasdiluted ten times in ethanol to prepare 1 mM solution of arachidonicacid. Arachidonic acid acts as a substrate. 10 μl of the 1 mM solutionof arachidonic acid was added to each well and incubated at CO₂incubator at 37° C. for 30 minutes. The cell solution of each well wasplaced in a centrifuge test tube and centrifuged at 10,000 rpm at 4° C.for 5 minutes. The concentration of PGE2 in the collected cells and thesupernatant was quantified by means of a monoclonal kit (CaymanChemicals). The percentages of PGE2 inhibition in a group of the testcompound-treated cells in relation to a group of the DMSO-treated cellswere calculated. Based on the calculated values, the COX-1 inhibitoryactivities were evaluated.

b. Assay for the COX-2 Inhibitory Activity Using RAW 264.7 Cell Line

2×10⁶ cells of RAW 264.7 cell line (Korean Cell Line Bank, Seoul, Korea,Accession Number: 40071) were inoculated into each well of 12-wellplates. Each well was treated with 250 μM of aspirin and incubated at37° C. for 2 hours. After the culture media were replaced with newculture media, the new culture media were treated with a test compound(10 nM) and incubated for 30 minutes. Then, each well was treated withinterferon γ (100 units/ml) and lipopolysaccharide (LPS, 100 ng/ml) andincubated for 18 hours. The culture media were transferred to other testtubes. The concentration of PGE2 was quantified by means of the EIA kit(Cayman Chemicals).

2) Test Results

The test results are presented in Table 1 below. The percentages of theCOX inhibition were calculated according to the following equation:% Inhibition=(concentration of PGE2 in test compound-untreatedsample−concentration of PGE2 in test compound-treatedsample)/(concentration of PGE2 in test compound-untreated sample)×100

TABLE 1 Cyclooxygenase (COX) Inhibition (%) Samples COX-1 (1 μM) COX-2(10 nM) Reference (Valdecoxib) 28.8 5.47 Example 16 35.5 11.2 Example 1748.8 10.5 Example 18 19.5 6.7 Example 19 37.4 12.3 Example 20 26.4 11.0Example 21 25.7 12.6 Example 22 11.1 36.4 Example 23 13.2 35.1 Example24 16.4 31.2 Example 25 23.2 27.8 Example 26 44.5 13.5 Example 27 11.211.5 Example 28 21.2 10.5 Example 29 17.7 11.1 Example 30 16.4 13.2Example 31 15.5 16.4 Example 32 21.4 11.5 Example 33 23.7 10.5 Example34 31.2 9.5 Example 35 23.4 16.1 Example 36 27.0 17.2 Example 37 12.022.3 Example 38 17.4 33.1 Example 39 15.5 20.7 Example 40 16.2 16.2Example 41 27.7 15.5 Example 42 26.6 13.3 Example 43 30.4 16.7 Example44 27.2 14.5 Example 45 23.4 13.3 Example 46 34.2 12.2 Example 47 25.410.6 Example 48 26.4 9.8 Example 49 33.1 24.5 Example 50 28.0 16.1Example 51 21.4 23.4 Example 52 34.3 33.1 Example 53 20.4 16.2 Example54 26.4 15.5 Example 55 33.1 16.2 Example 56 37.2 27.7 Example 57 21.426.6 Example 58 34.3 30.4 Example 59 22.6 27.2 Example 60 23.4 23.4Example 61 33.1 34.2 Example 62 26.0 25.4 Example 63 22.6 26.4 Example64 23.4 33.1

3) Evaluation

The in vitro test results about the percentages of the COX-1 and COX-2inhibition are listed in Table 1.

As shown in Table 1, inhibition (%) ratios of COX-2 to COX-1 in Examples16 to 64 were significantly higher than that in the reference,Valdecoxib. This indicates that selective inhibition of COX-2 to COX-1of the present compound is superior to that of the reference.

INDUSTRIAL APPLICABILITY

As apparent from the above description, the 1,2,4-triazole derivativeaccording to the present invention is an alternative drug forconventional nonsteroidal anti-inflammatory agents and is expected to beuseful for treating patients with peptic ulcer disease, gastritis,regional enteritis, ulcerative colitis, diverticullitis, gastrorrhagia,or hypoprothrombinemia.

While the present invention has been particularly shown and describedwith reference to exemplary embodiments thereof, it will be understoodby those of ordinary skill in the art that various changes in form anddetails may be made therein without departing from the spirit and scopeof the present invention as defined by the following claims.

1. A 1,2,4-triazole derivative represented by formula 1:

wherein: X represents methyl or amino; Ar represents phenyl or phenylsubstituted with one or more radicals selected from the group consistingof C₁-C₆ alkoxy and halogen; A represents O or S; and R represents H,C₁-C₆ alkyl, trifluoro C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkylsubstituted with cyano or halogen, propagyl, allyl, or benzyl; or anon-toxic salt thereof.
 2. The 1,2,4-triazole derivative according toclaim 1, which is selected from the group consisting of:4-(3-mercapto-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;4-(3-hydroxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;4-[3-hydroxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-hydroxy-5-(4-ethoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-hydroxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-hydroxy-5-(4-bromophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-hydroxy-5-(3-fluoro-4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;1-(4-methanesulfonylphenyl)-5-phenyl-1H-1,2,4-triazole-3-ol;1-(4-methanesulfonylphenyl)-5-(4-methoxyphenyl)-1H-1,2,4-triazole-3-ol;4-(3-methoxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;4-[3-methoxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-methoxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-methoxy-5-(4-bromophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-methoxy-5-(3-fluoro-4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-(3-methylthio-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;4-(3-ethoxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;4-[3-ethoxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-ethoxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-ethoxy-5-(3-fluoro-4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-(3-ethylthio-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;4-[3-propoxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-propoxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-cyclopentyloxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-cyclopentyloxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-cyclohexyloxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-cyclohexyloxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-(3-isopropoxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;4-[3-isopropoxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-isopropoxy-5-(−4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-(3-isopropylthio-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;4-(3-allyloxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;4-[3-allyloxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-allyloxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-cyanomethoxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-cyanomethoxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-(3-benzyloxy-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;4-[3-benzyloxy-5-(3-fluoro-4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-(2-chloroethoxy)-5-phenyl-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-(2,2,2-trifluoroethoxy)-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-(2,2,2,-trifluoroethoxy)-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-cyclopropoxy-5-phenyl-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-prop-2-ynyloxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-[3-prop-2-ynyloxy-5-(4-fluorophenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide;4-(3-propy-2-nylthio-5-phenyl-1,2,4-triazole-1-yl)-benzenesulfonamide;1-(4-methanesulfonylphenyl)-3-methoxy-5-phenyl-1H-1,2,4-triazole;1-(4-methanesulfonylphenyl)-3-methoxy-5-(4-methoxyphenyl)-1H-1,2,4-triazole;1-(4-methanesulfonylphenyl)-3-ethoxy-5-phenyl-1H-1,2,4-triazole;1-(4-methanesulfonylphenyl)-3-ethoxy-5-(4-methoxyphenyl)-1H-1,2,4-triazole;1-(4-methanesulfonylphenyl)-3-isopropoxy-5-phenyl-1H-1,2,4-triazole; and1-(4-methanesulfonylphenyl)-3-isopropoxy-5-(4-methoxyphenyl)-1H-1,2,4-triazole;or a non-toxic salt thereof.
 3. A method for preparing a 1,2,4-triazolederivative of formula 1b

wherein: X represents methyl or amino; Ar represents phenyl or phenylsubstituted with one or more radicals selected from the group consistingof C₁-C₆ alkoxy and halogen; A represents O or S; and R′ representsC₁-C₆ alkyl, trifluoro C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkylsubstituted with cyano or halogen, propagyl, allyl, or benzyl: whichcomprises reacting a compound of formula 1a

wherein: X, Ar, and A are as defined in formula 1b with R′—Br or R′—I inthe presence of a at least one base selected from the group consistingof triethyl amine, trimethyl amine, tripropyl amine, pyridine,imidazole, sodium acetate, sodium hydroxide, sodium hydride, potassiumhydroxide, sodium carbonate, and potassium carbonate, wherein R′ is asdefined in formula 1b.